Pharmaceutical composition comprising salbutamol

Abstract

The present invention relates to a pharmaceutical composition consisting of an active ingredient based on a pharmaceutically acceptable salbutamol salt, 1,1-difluoroethane (R-152a) and ethanol. The invention also relates to the use thereof in the treatment of respiratory disorders, to a canister comprising same and also to a metered-dose inhaler provided with such a canister. The invention lastly relates to the uses of this pharmaceutical composition and of this canister in a metered-dose inhaler.

Description

[0001] Description

[0002] Title: Pharmaceutical composition comprising salbutamol

[0003] Technical field

[0004] The present invention relates to a pharmaceutical composition which is suitable for use in the treatment of respiratory disorders and which comprises an active ingredient based on a salbutamol salt, in particular salbutamol sulfate, and a propellant gas formed by 1,1-difluoroethane.

[0005] The invention also relates to a cartridge comprising this pharmaceutical composition as well as to a metered-dose aerosol provided with such a cartridge.

[0006] The invention finally relates to the uses of this pharmaceutical composition and of this cartridge in a metered-dose aerosol.

[0007] State of the prior art

[0008] Salbutamol and its derivatives are active ingredients known as bronchodilators in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD).

[0009] Pharmaceutical compositions comprising salbutamol or one of its derivatives are conventionally delivered to patients by means of a metered dose inhaler (MDI).

[0010] A metered-dose inhaler is an administration device equipped with a cartridge containing the pharmaceutical composition, a metering valve for dispensing a controlled quantity of pharmaceutical composition containing the active ingredient and an applicator for exerting pressure on the metering valve and equipped with a mouthpiece.

[0011] The pharmaceutical composition comprises a propellant gas in which the active ingredient is dissolved, suspended or dispersed, and optionally one or more other compounds which may be chosen in particular from surfactants, polar excipients and preservatives. The choice of propellant gas used in metered-dose inhalers for pharmaceutical purposes has evolved over the years.

[0012] Given their deleterious effects on the ozone layer, chlorofluorocarbons (CFCs), long used, have been abandoned in favor of hydrofluorocarbons (HFCs), more recently referred to as hydrofluoroalkanes (HFAs), such as 1,1,1,2-tetrafluoroethane (HFC-134a, HFA-134a or R-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea, HFA-227ea or R-227ea) which are compounds that do not have any harmful effects on the ozone layer or human toxicity.

[0013] However, these hydrofluoroalkanes R-134a and R-227ea being characterized by a high global warming potential (GWP) with a significant impact on the greenhouse effect, pharmaceutical compositions comprising salbutamol, or one of its derivatives, and an alternative propellant gas have been proposed.

[0014] Thus, documents WO 2013 / 054137 Al, WO 2014 / 170689 Al and WO 2013 / 054135 Al, respectively referenced [1] to [3] in the remainder of this description, describe the use of a particular hydrofluorocarbon (HFC) or hydrofluoroalkane (HFA), 1,1-difluoroethane (HFC-152a, HFA-152a or R-152a) in pharmaceutical compositions comprising salbutamol sulfate.

[0015] Document US 2007 / 041911 A1, referenced [4], incidentally cites HFC-152a among a number of hydrofluorocarbons that may be used as a propellant in pharmaceutical compositions comprising an acid addition salt of salbutamol, a co-solvent and an organic or inorganic acid. However, document [4] does not describe any example of a pharmaceutical composition specifically using R-152a.

[0016] The recent document US 2021 / 244688 A1, referenced [5], describes pharmaceutical compositions comprising salbutamol, alone or in combination with at least one long-acting muscarinic antagonist and / or at least one corticosteroid, as well as HFA-152a as propellant gas. However, in document [5], the salbutamol used is a so-called "base" salbutamol, which is defined as excluding all pharmaceutically acceptable derivatives of salbutamol, in particular salbutamol salts. More particularly, the pharmaceutical compositions described in documents [1] and [2] comprise salbutamol sulfate, R-152a as well as one or more surfactants whose role is to help disperse the particles of active ingredient in the propellant gas.

[0017] In document [1], this surfactant is oleic acid whereas, in document [2], this surfactant comprises at least one compound other than oleic acid.

[0018] Although not particularly preferred variants, the pharmaceutical compositions described in documents [1] and [2] may also comprise one or more polar excipients, such as ethanol, which are described as having the effect of solubilizing the surfactant in the propellant and / or inhibiting the deposition of particles of active ingredient on the surfaces of the cartridge.

[0019] In contrast, the pharmaceutical compositions described in document [3] do not include a surfactant on the grounds that surfactants would not be desirable and there would be an advantage in forming a stable suspension without the use of a surfactant. Document [3] states that the use of the propellant gas R-152a makes it possible to prepare pharmaceutical compositions free of surfactants and polar excipients which nevertheless exhibit good pharmaceutical performance when delivered from a drug delivery device such as a metered dose inhaler (MDI).

[0020] However, the inventors found that pharmaceutical compositions consisting solely of salbutamol sulfate and R-152a did not allow the expected aerosolization performance to be obtained.

[0021] It is therefore on the basis of this observation and with a constant concern to improve the aerosolization properties and, therefore, the therapeutic properties conferred by pharmaceutical compositions intended for the treatment of respiratory disorders that the present invention is based. Statement of the invention

[0022] This and other aims are achieved, firstly, by a pharmaceutical composition of the aforementioned type, that is to say which comprises an active ingredient based on salbutamol and 1,1-difluoroethane as propellant gas.

[0023] According to the invention, the pharmaceutical composition consists of the following compounds:

[0024] (a) an active ingredient based on a pharmaceutically acceptable salt of salbutamol,

[0025] (b) 1,1-difluoroethane (R-152a), and

[0026] (c) ethanol.

[0027] The inventors have found that, unexpectedly and surprisingly, a pharmaceutical composition which comprises only a salbutamol salt, R-152a and ethanol makes it possible to achieve aerosolization performances which are much higher than those of a pharmaceutical composition comprising only a salbutamol salt and R-152a as described in document [3], these remarkable aerosolization performances being furthermore stable over time.

[0028] This result is all the more unexpected as it goes against the teachings of documents [1] to [3] which recommend limiting or even avoiding the use of ethanol in pharmaceutical compositions based on salbutamol sulfate and R-152a. These documents report in particular that ethanol can cause unacceptable irritation of the mouth and throat, particularly in young patients, and / or cause coarse spraying of the pharmaceutical compositions characterized by droplet sizes that are too large to achieve acceptable penetration into the deep bronchioles of the lung.

[0029] In an advantageous variant of the pharmaceutical composition according to the invention, the active ingredient (a) is a salbutamol salt.

[0030] In a preferred variant of the invention, this active ingredient (a) is salbutamol sulfate. The active ingredient (a) is advantageously in the form of particles whose size is suitable for delivery by inhalation of the pharmaceutical composition in which it is contained. Conventionally, the median diameter of the particles of active ingredient (a), commonly noted Dvso, is less than or equal to 6 pm, which means that at least 50% by volume of the particles of active ingredient (a) have a diameter less than or equal to 6 pm.

[0031] This median diameter of the particles of active ingredient (a) is advantageously less than or equal to 5 pm, preferably between 0.5 pm and 5 pm and, more preferably, between 1 pm and 4 pm.

[0032] In a variant of the composition according to the invention, the mass proportion of active ingredient (a) is between 0.05% and 0.5% by mass relative to the total mass of the pharmaceutical composition. This mass proportion is advantageously between 0.1% and 0.4% by mass and, preferably, between 0.2% and 0.35% by mass relative to the total mass of the pharmaceutical composition.

[0033] In a variant of the composition according to the invention, the mass proportion of 1,1-difluoroethane (b) is between 89.5% and 99.9% by mass relative to the total mass of the pharmaceutical composition.

[0034] In another variant, the mass proportion of 1,1-difluoroethane (b) is between 94.5% and 99.9% by mass relative to the total mass of the pharmaceutical composition. This mass proportion is advantageously between 96.6% and 99.7% by mass and, preferably, between 97.65% and 99.3% by mass relative to the total mass of the pharmaceutical composition.

[0035] In a variant of the composition according to the invention, the mass proportion of ethanol (c) is between 0.05% and 10% by mass relative to the total mass of the pharmaceutical composition.

[0036] In another variant, the mass proportion of ethanol (c) is between 0.05% and 5% by mass relative to the total mass of the pharmaceutical composition. The aerosolization performance of the pharmaceutical composition according to the invention can be achieved with a relatively low mass proportion of ethanol, which does not present any danger to the health of the patient, even a young patient.

[0037] The mass proportion of ethanol may advantageously be between 0.2% and 3% by mass and, preferably, between 0.5% and 2% by mass relative to the total mass of the pharmaceutical composition.

[0038] The present invention relates, secondly, to a pharmaceutical composition for use in the treatment of patients suffering from or likely to suffer from respiratory disorders.

[0039] According to the invention, this pharmaceutical composition, which is used in the treatment of respiratory disorders, is as defined above, that is to say that it consists of the following compounds:

[0040] (a) an active ingredient based on a pharmaceutically acceptable salt of salbutamol,

[0041] (b) 1,1-difluoroethane (R-152a), and

[0042] (c) ethanol.

[0043] The characteristics described above in connection with the pharmaceutical composition and, in particular, the characteristics relating to the active ingredient as well as to the mass proportions of the different compounds forming this pharmaceutical composition, are of course applicable to the present use in the treatment of respiratory disorders.

[0044] Such respiratory disorders can be asthma or chronic obstructive pulmonary disease (COPD).

[0045] Within the scope of the present invention, patients may be treated by administering a therapeutically effective amount of a pharmaceutical composition as defined above.

[0046] The present invention relates, thirdly, to a cartridge comprising a pharmaceutical composition as well as to a metered-dose aerosol comprising such a cartridge. According to the invention, this pharmaceutical composition is as defined above, that is to say that it consists of the active ingredient (a), R-152a as propellant gas and ethanol, the characteristics relating to these compounds being able to be taken alone or in combination.

[0047] The present invention relates, fourthly, to the use of a pharmaceutical composition and / or a cartridge as defined above in a metered dose inhaler (MDI), such a device being conventionally used to deliver pharmaceutical compositions comprising an active ingredient based on salbutamol or a pharmaceutically acceptable salt thereof.

[0048] Other characteristics and advantages of the invention will appear more clearly on reading the additional description which follows, which relates to examples of pharmaceutical compositions as well as to the evaluation of their in vitro aerosolization performances, two pharmaceutical compositions, noted C4 and C4', being in accordance with the invention, the others being comparative pharmaceutical compositions in accordance with the teachings of documents [1] and [3], noted C1 to C3 and C3'.

[0049] Brief description of the figures

[0050] Figure 1 represents the graphs illustrating the deposited fraction of salbutamol particles (expressed in %) from doses or puffs of pharmaceutical compositions C1 to C4 as measured at T0, as a function of the stages of the NGI pharmaceutical impactor.

[0051] Figures 2A, 2B and 2C represent the graphs illustrating the deposited fraction of salbutamol particles (expressed in %) from doses or puffs of the pharmaceutical compositions C3' and C4' as respectively measured at T0, T3M and T6M, as a function of the stages of the NGI pharmaceutical impactor.

[0052] Figure 3 reproduces the graphs of Figures 2A, 2B and 2C illustrating the deposited fraction of salbutamol particles (expressed in %) originating from the doses of the pharmaceutical composition C4' in accordance with the invention as measured at T0, at T3M and at T6M, as a function of the stages of the pharmaceutical impactor NGI. Figure 4 reproduces the graphs of Figures 2A, 2B and 2C illustrating the deposited fraction of salbutamol particles (expressed in %) originating from the doses of the comparative pharmaceutical composition C3' as measured at T0, at T3M and at T6M, as a function of the stages of the pharmaceutical impactor NGI.

[0053] Detailed description of specific embodiments

[0054] Example 1

[0055] The aerosols tested were manufactured with the same batches of compounds, aluminum cartridges, and metering valves.

[0056] Four pharmaceutical compositions C1 to C4 were prepared from the following amounts of salbutamol sulfate (median diameter of the order of 2 pm), oleic acid and ethanol mentioned in Table 1 below.

[0057] Table 1

[0058] Where appropriate, oleic acid or ethanol was first manually introduced into four separate sets of cartridges followed by salbutamol sulfate.

[0059] A metering valve was then crimped onto each of the cartridges with suitable equipment, and then the propellant gas R-152a was introduced using suitable equipment via the metering valve to achieve a total mass of pharmaceutical composition of 11375 mg.

[0060] The aerosols thus packaged were then stored in an inverted position (valve downwards) for a quarantine period of at least one week. At the end of this quarantine period, an aerodynamic particle size distribution (APSD) measurement test was carried out.

[0061] This T0 test, which consists of evaluating the aerodynamic size of the active ingredient particles exiting the valve, was carried out using a multi-stage pharmaceutical impactor allowing approximate modeling of the bronchial tree. In this case, the pharmaceutical impactor used was the Next Generation Impactor (NGI) which corresponds to device E of the European Pharmacopoeia.

[0062] More specifically, the tests were carried out at a flow rate of 30 L / min, expelling 5 doses of each of the compositions Cl to C4 into the NGI impactor.

[0063] The graph in Figure 1 represents the fraction of salbutamol deposited in the throat and mouth (denoted T&M) and on each of the stages of the impactor (denoted SI to S8).

[0064] To ensure optimal therapeutic efficacy, the fraction deposited on stages 3 to 6, noted S3 to S6, and more particularly on S4 and S5, must be maximized.

[0065] Figure 1 shows that the pharmaceutical composition C4 according to the invention, which comprises 1% by mass of ethanol, effectively makes it possible to optimize this therapeutic efficacy since the fraction of salbutamol deposited on these stages S3 to S6, and in particular on stages S4 and S5, is very clearly higher than the fractions of salbutamol deposited on these same stages from the comparative pharmaceutical compositions C1 to C3, this phenomenon being more marked from the comparative pharmaceutical composition C3. Compared to the data obtained with the comparative pharmaceutical compositions C1 and C2, it is observed that the implementation of the pharmaceutical composition C4 in accordance with the invention allows a displacement of the fine particles from stage S3 to stage S4 and especially to stage S5 which are smaller in fine particle size.

[0066] This finding is all the more surprising since: on the one hand, the comparative pharmaceutical compositions C1 and C2 respectively comprise mass proportions of 0.25% by mass and 0.3% by mass which fall within the preferred range of 0.2% by mass to 1.0% by mass of surfactant, in this case oleic acid, taught by document [1], and

[0067] - on the other hand, the comparative pharmaceutical composition C3, which does not include surfactant or ethanol, is described by document [3] as having good pharmaceutical performance.

[0068] The therapeutic performances of the pharmaceutical composition in accordance with the invention are, in addition, corroborated by the data of fractions of fine particles reported in table 2 below, table in which the quantities of oleic acid or ethanol present in the pharmaceutical compositions C1, C2 and C4 have been reported in mass proportion (% by mass).

[0069] Table 2

[0070] Example 2

[0071] As in Example 1, the metered-dose inhalers were prepared with the same references of compounds, aluminum cartridges and metering valves, according to an identical operating protocol.

[0072] In a first step, a metering valve was crimped onto each of the cartridges using suitable equipment.

[0073] In a second stage, two separate series of metered-dose aerosols were filled in two stages using pilot equipment by introduction via the metering valve:

[0074] - a concentrated suspension comprising 30.125 mg of salbutamol sulfate (median diameter of the order of 5 pm), a reduced quantity of propellant gas R-152a and, where appropriate, the mass proportion of ethanol indicated in Table 3 below, relative to the total mass of pharmaceutical composition, then

[0075] - a sufficient quantity of propellant gas R-152a to reach a total mass of pharmaceutical composition of 9.57 g.

[0076] Table 3

[0077] Three series of aerodynamic particle size distribution (APSD) measurement tests were carried out at a flow rate of 30 L / min, expelling 5 doses of each of the pharmaceutical compositions C3' and C4' into the NGI impactor, as in Example 1 above.

[0078] A first series of aerodynamic particle size distribution measurement tests was conducted on pharmaceutical compositions C3' and C4' as obtained at T0, i.e. at the end of the quarantine period mentioned in example 1.

[0079] The results of this first series of tests at T0 are reported in Figure 2A.

[0080] A second series of aerodynamic particle size distribution measurement tests was conducted on these same pharmaceutical compositions C3' and C4' as obtained at T3M, i.e. after storage for a period of three months from T0 of the metered-dose aerosols comprising said compositions C3' and C4', these metered-dose aerosols being placed, during these three months, in an inverted position (valve downwards) under respective temperature and relative humidity conditions of 40°C and 75% which comply with the guidelines of the International Council for Harmonisation for Pharmaceutical Quality (ICH QI Stability Guidelines).

[0081] The results of this second series of tests at T3M are shown in Figure 2B. A third series of aerodynamic particle size distribution measurement tests was conducted on these same pharmaceutical compositions C3' and C4' as obtained at T6M, i.e. after storage for a period of six months from T0 of the metered-dose aerosols comprising said compositions C3' and C4', these metered-dose aerosols being placed, during these six months, in an inverted position and under the temperature and relative humidity conditions described in the preceding paragraph.

[0082] The results of this third series of tests at T6M are reported in Figure 2C.

[0083] Figures 3 and 4 group together the graphs of Figures 2A to 2C obtained with the pharmaceutical composition C4' in accordance with the invention (Figure 3) and with the comparative pharmaceutical composition C3' (Figure 4). It is specified that this comparative pharmaceutical composition C3' is in accordance with the teaching of document [3].

[0084] The graphs in Figures 2A to 2C, 3 and 4 represent the fractions of salbutamol deposited, on the one hand, at the throat and mouth (T&M) and, on the other hand, on each of the eight stages of the impactor (denoted SI to S8).

[0085] To ensure optimal therapeutic efficacy, the fractions deposited on stages S3 to S6 must be maximized and the fraction deposited at the T&M level minimized.

[0086] Figures 2A, 2B and 2C show that the pharmaceutical composition C4' according to the invention, which comprises 1% by mass of ethanol, effectively makes it possible to optimize this therapeutic efficacy.

[0087] On the one hand, with reference to Figure 2A, it can be seen that the sum of the salbutamol fractions deposited at T0 on stages S3 to S6 from the pharmaceutical composition C4' is significantly greater than the sum of the salbutamol fractions deposited at T0 on these same stages S3 to S6 from the comparative pharmaceutical composition C3'. This observation is even more marked if we refer to the graphs in Figures 2B and 2C.

[0088] On the other hand, and still with reference to Figure 2A, it is observed that the fraction of salbutamol deposited at T0 from the pharmaceutical composition C4' according to the invention at the T&M level is of the order of 35% and therefore much lower than the fraction of salbutamol deposited at TO from the comparative pharmaceutical composition C3', which is of the order of 45%. If we refer to Figures 2B and 2C, we observe that this rate of 35% is maintained at T3M and T6M with the pharmaceutical composition C4' according to the invention while it increases to reach values ​​of the order of 70% with the comparative composition C3'.

[0089] Figure 3 shows that the pharmaceutical composition C4' according to the invention retains this optimized therapeutic efficacy over time, even after six months of storage at 40°C and 75% relative humidity. Indeed, the graphs in this figure 3 are practically superimposable, reflecting the fact that the sum of the salbutamol fractions deposited on stages S3 to S6 as well as the salbutamol fraction deposited at level T&M are similar, or even identical, to TO, T3M and T6M. In other words, the pharmaceutical composition C4' according to the invention is characterized by stable aerosolization performances over time.

[0090] On the contrary, if we refer to Figure 4, we observe that the therapeutic efficacy is strongly degraded for the comparative pharmaceutical composition C3' at least already after three months of storage at 40°C and 75% relative humidity (T3M) and, a fortiori, at T6M.

[0091] Bibliography

[0092] [1] WO 2013 / 054137 Al

[0093] [2] WO 2014 / 170689 Al

[0094] [3] WO 2013 / 054135 Al

[0095] [4] US 2007 / 041911 Al

[0096] [5] US 2021 / 244688 Al

Claims

1. A pharmaceutical composition comprising the following compound: (a) salbutamol sulfate as the active ingredient; (b) 1,1-difluoroethane (R-152a), and (c) Ethanol.

2. 2. The pharmaceutical composition according to claim 1, wherein the weight proportion of the active ingredient (a) is between 0.05% and 0.5% by weight, advantageously between 0.1% and 0.4% by weight and preferably between 0.2% and 0.35% by weight, based on the total weight of the pharmaceutical composition.

3. 2. The pharmaceutical composition according to claim 1, wherein the mass proportion of 1,1-difluoroethane (b) is 89.5% to 99.9% by weight, in particular 94.5% to 99.9% by weight, advantageously 96.6% to 99.7% by weight, and preferably 97.65% to 99.3% by weight, based on the total mass of the pharmaceutical composition.

4. 2. The pharmaceutical composition according to claim 1, wherein the weight proportion of ethanol (c) is from 0.05% to 10% by weight, in particular from 0.05% to 5% by weight, advantageously from 0.2% to 3% by weight, and preferably from 0.5% to 2% by weight, based on the total weight of the pharmaceutical composition.

5. A pharmaceutical composition according to any one of claims 1 to 4 for use in the treatment of a respiratory disorder such as asthma or chronic obstructive pulmonary disease (COPD).

6. A canister containing the pharmaceutical composition according to any one of claims 1 to 4.

7. A metered dose inhaler (MDI) comprising the canister of claim 6.

8. Use of a pharmaceutical composition according to any one of claims 1 to 4 or of a canister according to claim 6 in a metered dose inhaler (MDI).

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